The effect of keratinocyte growth factor on healing of manifest radiation ulcers in mouse tongue epithelium.

Abstract

The purpose of this study was to examine the effect of recombinant human keratinocyte growth factor (rHuKGF) on clinically manifest acute oral mucositis. The animal model utilized in this investigation was ventral tongue epithelium of C3H/Neu mice. In a first experiment, graded single doses were applied in order to define dose effect and time course of acute mucosal ulceration, as a clinically relevant endpoint. Irradiation was given to a 3 x 3 mm2 test field in the centre of the ventral tongue with 25 kV X-rays. A single dose of 18 Gy, i.e. a dose after which ulceration is expected in more than 99% of the animals, was applied in subsequent experiments. In the study group of 20 animals, rHuKGF was applied at a daily dose of 5 mg/kg subcutaneously from the time of first diagnosis of ulcer for a maximum of 5 days. In the control group, phosphate-buffered saline was used as a placebo. The time course of ulceration, i.e. individual ulcer duration, was analysed in both the control group without rHuKGF and the study group. Irradiation with graded single doses yielded an ED50 of 11.5 +/- 0.7 Gy (logit analysis). In responding animals, the latent time to first diagnosis of ulceration and the individual ulcer duration were independent of dose. Mean latency (+/- standard deviation) was 10.5 +/- 0.5 days, mean ulcer duration 3.9 +/- 0.6 days for doses 11, 13 and 16 Gy. After a dose of 18 Gy, 39 animals developed ulceration after a mean latency of 9.3 +/- 0.3 days (control and KGF-treated). The average ulcer duration was 4.2 +/- 0.9 days in the placebo group and 4.8 +/- 0.8 days in the KGF group (P = 0.02). We conclude that when rHuKGF treatment is delayed until radiation-induced ulcers are manifest, the therapeutic activity previously reported with other treatment schedules was not observed and there was a slight prolongation of duration of ulceration. These data suggest that during tumour radiotherapy, effective rHuKGF therapy schedules should include administration before the onset of ulcerative mucositis.